Cancer is a devastating group of diseases, among the most common causes of death for Americans. Current therapies for advanced disease are highly toxic and all too often ineffective. Our group has recently demonstrated a powerful innate inducible ability of human cells to recognize and respond to damaged DNA, a characteristic of cancer cells. Moreover, we have shown that DNA fragments homologous to the telomere 3' strand (tandem repeats of TTAGGG) activate the same protective DNA damage responses, presumably by mimicking the physiologic DNA damage signal of telomere loop disruption that exposes the 3' overhang. The telomere-homologous oligonucleotides (T-oligos) induce and activate various DNA damage response and tumor suppressor pathways in cells, including those mediated by ATM, p53, p73, p95/Nbs-1, BRACA1, E2F1 and p16. In normal cells, the T-oligos induce transient cell cycle arrest and promote differentiated behaviors normally evoked by DNA damage, such as enhanced melanogenesis (tanning) in melanocytes and immunomodulatory cytokine release in keratinocytes. However, compared to normal cells, malignant cells have exaggerated responses that lead either to apoptosis or a permanently non-dividing state (senescence), or to a combination of these responses, depending on cell type. Working with malignant human cell lines of multiple lineages, we have shown all to be dramatically responsive to T-oligos in vitro. Using a SCID mouse model for human melanoma, we demonstrated that 48 hours pretreatment of the aggressive MM-AN cell line with T-oligo reduces its local and metastatic growth potential by 85-95% and leads to differentiation of remaining melanoma cells. We have further shown dramatic regression or disappearance of previously untreated established MM-AN flank melanoma nodules in SCID mice following either intralesional, intravenous, or intraperitoneal administration of T-oligos. Patents protecting the use of T-oligos as a cancer therapy are pending and have been licensed by Boston University to SemaCo, Inc, to encourage their commercialization. The goal of this STTR grant application is to confirm and extend our previous in vitro data, to select an optimal T-oligo for clinical testing, to perform dosing ranging (safety) studies in mice, and then to characterize the therapeutic effects of T-oligos in mouse models of human melanoma and breast carcinoma, using GLP protocols to generate data on which an Investigational New Drug (IND) application can be based.